Abstract

Introduction

The breast microenvironment can either retard or accelerate the events associated
with progression of latent cancers. However, the actions of local physiological mediators
in the context of breast cancers are poorly understood. Serotonin (5-HT) is a critical
local regulator of epithelial homeostasis in the breast and other organs. Herein,
we report complex alterations in the intrinsic mammary gland serotonin system of human
breast cancers.

Results

In the context of the normal mammary gland, 5-HT acts as a physiological regulator
of lactation and involution, in part by favoring growth arrest and cell death. This
tightly regulated 5-HT system is subverted in multiple ways in human breast cancers.
Specifically, TPH1 expression undergoes a non-linear change during progression, with
increased expression during malignant progression. Correspondingly, the tightly regulated
pattern of 5-HT receptors becomes dysregulated in human breast cancer cells, resulting
in both ectopic expression of some isoforms and suppression of others. The receptor
expression change is accompanied by altered downstream signaling of 5-HT receptors
in human breast cancer cells, resulting in resistance to 5-HT-induced apoptosis, and
stimulated proliferation.

Conclusions

Our data constitutes the first report of direct involvement of 5-HT in human breast
cancer. Increased 5-HT biosynthetic capacity accompanied by multiple changes in 5-HT
receptor expression and signaling favor malignant progression of human breast cancer
cells (for example, stimulated proliferation, inappropriate cell survival). This occurs
through uncoupling of serotonin from the homeostatic regulatory mechanisms of the
normal mammary epithelium. The findings open a new avenue for identification of diagnostic
and prognostic markers, and valuable new therapeutic targets for managing breast cancer.